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WO2025024449A1 - Procédés et intermédiaires pour la synthèse de mrtx1133 - Google Patents

Procédés et intermédiaires pour la synthèse de mrtx1133 Download PDF

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WO2025024449A1
WO2025024449A1 PCT/US2024/039161 US2024039161W WO2025024449A1 WO 2025024449 A1 WO2025024449 A1 WO 2025024449A1 US 2024039161 W US2024039161 W US 2024039161W WO 2025024449 A1 WO2025024449 A1 WO 2025024449A1
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Prior art keywords
aprotic solvent
produce
group
mrtx1133
base
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Tawfik Gharbaoui
Thomas SCATTOLIN
Cheng Chen
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Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

Definitions

  • the present invention relates to new synthetic routes for synthesis of MRTX1133.
  • KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP -bound active
  • cellular proliferation e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401.
  • KRas The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640).
  • Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 - 30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428).
  • KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8): 818-831. Dataset Version 4).
  • KRas The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy.
  • MRTX1133 is described, for example, in Example 252 of PCT Application WO 2021/041671.
  • the present invention in one embodiment, provides new and improved methods of making MRTX1133.
  • the invention provides a method of synthesizing MRTX1133 (4-(4- ((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol), comprising step (a): a) reacting triisopropyl silyl chloride (TIPSC1) and a base in an aprotic solvent to produce a final compound of step (a) with the following structure:
  • TIPSC1 triisopropyl silyl chloride
  • step (a) is carried out at a temperature from about 0 °C to about 25 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether, dimethylformamide (DMF), 1,4-dioxane, dimethyl sulfoxide (DMSO), and N-Methyl-2-pyrrolidone (NMP).
  • toluene anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether,
  • the base is an organic base.
  • the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), tri ethylenediamine (DABCO), and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DIPEA Diisopropylethylamine
  • EtsN triethylamine
  • DABCO tri ethylenediamine
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • An inorganic base can be used with any alkali such as lithium, sodium and potassium.
  • the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).
  • the method further comprises step (b): b) reacting activating agent and a base in an aprotic solvent to produce a final compound of step (b) with the following structure: wherein R is a leaving group.
  • the leaving group is CF3.
  • the leaving group is determined by the activating agent that is used in the reaction.
  • the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SO2X (where R can be, but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br), anhydride (trifluoromethanesulfonic (triflic) anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagent R'-N-Tfz (where R 1 is phenyl, 5-chloro-2-pyridine, 2-pyridine).
  • R-SO2X sulfonyl halide
  • R can be, but is not limited tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br
  • anhydride trifluoromethanesulfonic (trif
  • step (b) is carried out at a temperature of about 0°C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the base is an inorganic base.
  • the base is an organic base.
  • the organic base is selected from the group consisting of DIPEA, Et 3 N, DABCO, and DBU.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • An inorganic base can be used with any alkali such as lithium, sodium and potassium.
  • the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).
  • step (b) the activating agent is triflic anhydride.
  • the method further comprises step (c): c) reacting the final compound of step (b) with a ligand and a palladium catalyst in an aprotic solvent to produce a final compound of step (c) with the following structure:
  • step (c) is carried out at a temperature of between about 75 °C and about 80°C.
  • the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.
  • the palladium catalyst is selected from the group consisting of palladium (II) acetate (Pd(OAc)2) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cb).
  • the step can comprise additional bases and other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.
  • TAA triethylamine
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.
  • the organic base is selected from the group consisting of DIPEA, Et 3 N, DABCO, and DBU.
  • the method further comprises step (d): the presence of a base and aprotic solvent to produce a final compound of step (d) with the following structure:
  • step (d) is carried out at a temperature from about -15 °C to about 12 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether, , DMF, 1,4-di oxane, DMSO, and NMP .
  • the base is an organic base.
  • the organic base is selected from the group consisting of DIPEA, Et 3 N, DABCO, and DBU.
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • An inorganic base can be used with any alkali such as lithium, sodium and potassium.
  • the inorganic base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS, LDA, and LiTMP.
  • the method further comprises step (e): e) reacting the final compound of step (d) with the final compound of step (c) in the presence of a palladium catalyst, tris potassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)-hydrochloride, and an aprotic solvent to produce a compound of the following structure:
  • step (e) is carried out at a temperature from about 60 °C to about 80 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.
  • the method further comprises step (f): f) reacting the final compound of step (e) with a fluoride salt in an aprotic solvent to produce a final compound of step (f) with the following structure:
  • step (f) is carried out at a temperature from about 25 °C to about 45 °C.
  • the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, di chloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.
  • the method further comprises step (g): g) reacting the final compound of step (f) with boron trifluoride acetonitrile in an aprotic solvent to produce a final compound of step (g) with the following structure: [0049] In one embodiment, step (g) is carried out at a temperature from about 25 °C to about 45 or
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diethylene glycol dimethyl ether, DMF, 1 ,4-dioxane, DMSO, and NMP.
  • the invention provides a method of synthesizing MRTX1133, comprising reacting with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • the invention provides a method of synthesizing MRTX1133 comprising: the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • the invention provides a method of synthesizing MRTX1133 comprising: , wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:
  • the invention provides a method of synthesizing MRTX1133 comprising: -reacting activating agent, an organic base in an aprotic solvent to produce: , wherein R is a leaving group;
  • R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:
  • the invention provides a method of synthesizing MRTX1133 comprising: triisopropyl silyl chloride (TIPSC1), a base, in an aprotic solvent to produce: p , g g p
  • R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:
  • the invention also encompasses each of the above steps by themselves (i.e., an embodiment that is directed to step (a); an embodiment that is directed to step (b); an embodiment that is directed to step (c), etc.), as well to combinations of the steps (i.e., an embodiment that is directed to step (a) and step (b); an embodiment that is directed to steps (a), (b), and (c),
  • the invention also provides a method of synthesizing MRTX1133 comprising,
  • TIPSC1 triisopropyl silyl chloride
  • the invention also provides novel compounds of the following structures:
  • the present invention relates to new synthetic routes for synthesizing MRTX1133, as well as to a novel intermediate used in the provided route.
  • KRas G12D refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Gly 12Cys.
  • KRas G12D-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation.
  • a non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.
  • MRTX1133 refers to the compound which has the name: 4-(4- ((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) and has the following structure:
  • MRTX1133 is described, for example, in Example 252 of PCT Application WO 2021/041671.
  • MRTX1133 encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.
  • the term “MRTX1133” includes salts of the above compound, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulf
  • LG refers to a leaving group and has the meaning conventionally associated with the term “leaving group” in synthetic organic chemistry; that is, an atom or group that is displaceable under alkylating or nucleophilic aromatic substitution conditions.
  • the term “leaving group” includes, but is not limited to, halogen, for example chlorine and bromide; alkanesulfonyloxys, for example methanesulfonyloxy and ethanesulfonyloxy; arenesulfonyloxys, for example benzylsulfonyloxy and tosyloxy; thienyloxy; dihalophosphinoyloxy; tetrahalophosphaoxy; perfluoroalkanesulfonyloxys, for example trifluoromethanesulfonyloxy and the like.
  • the leaving group should be selected so as to be chemically less reactive (except of course when the leaving group is bromine wherein it will be equally reactive)
  • R refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl , aralkyl, or arylalkyl.
  • alkyl is intended to mean a straight chain or branched aliphatic group having from 1 to 12 carbon atoms, alternatively 1-8 carbon atoms, and alternatively 1-6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • a “CO” alkyl (as in “C0-C3alkyl”) is a covalent bond.
  • alkenyl is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms.
  • alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkylene alkenylene
  • alkynylene alkynylene
  • alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
  • alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
  • cycloalkyl is intended to mean a saturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, alternatively having 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons.
  • the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.
  • cycloalkyl groups include, without limitation, cyclopenten-2- enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.
  • heteroalkyl is intended to mean a saturated or unsaturated, straight chain or branched aliphatic group, wherein one or more carbon atoms in the group are independently replaced by a heteroatom selected from the group consisting of O, S, and N.
  • aryl is intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example a C6-C14aromatic moiety, for example comprising one to three aromatic rings.
  • the aryl group is a C6-C10aryl group, alternatively a C6aryl group.
  • Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • aralkyl or "arylalkyl” are intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as “optionally substituted”, it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. Alternatively, the aralkyl group is (Cl-C6)alk(C6- C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • arylalkyl this term, and terms related thereto, is intended to indicate the order of groups in a compound as “aryl - alkyl”.
  • alkyl-aryl is intended to indicate the order of the groups in a compound as “alkyl-aryl”.
  • the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid,
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methyl
  • mineral acid refers to any acid derived from an inorganic compound that dissociates to produce hydrogen ions (H+) in water.
  • Nonlimiting examples of mineral acids include hydrogen halides of the general formula HX (where X is F, Cl, Br or I), nitric acid, phosphoric acid, sulfuric acid, boric acid and perchloric acid.
  • organic acid refers to any organic compound with acidic properties.
  • organic acids include sulfonic acids of the general formula RSO3H (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are define above), carboxylic acids (with one or several carboxylic acid sites) of the general formula RCO2H (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are define above).
  • Nonlimiting examples of organic acids are lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.
  • the present invention in one embodiment, provides new and improved methods of making MRTX1133.
  • the invention provides a method of synthesizing MRTX1133 (4-(4- ((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol), comprising step (a): a) reacting triisopropyl silyl chloride (TIPSC1) and a base in an aprotic solvent to produce a final compound of step (a) with the following structure: [0088] In one embodiment, step (a) is carried out at a temperature from about 0 °C to about 25 °C.
  • TIPSC1 triisopropyl silyl chloride
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl, diethylene glycol dimethyl, DMF, 1,4-dioxane, DMSO, and NMP .
  • the base is an organic base.
  • the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), tri ethylenediamine (DABCO), and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DIPEA Diisopropylethylamine
  • EtsN triethylamine
  • DABCO tri ethylenediamine
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • An inorganic base can be used with any alkali such as lithium, sodium and potassium.
  • the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).
  • the method further comprises step (b):
  • step (b) reacting activating agent and a base in an aprotic solvent to produce a final compound of step (b) with the following structure: wherein R is a leaving group.
  • the leaving group is CF3.
  • the leaving group is determined by the activating agent that is used in the reaction.
  • the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SO2X (where R can be, but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br), anhydride (trifluoromethanesulfonic (triflic) anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagent R'-N-Tfz (where R 1 is phenyl, 5-chloro-2-pyridine, 2-pyridine).
  • R-SO2X sulfonyl halide
  • R can be, but is not limited tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br
  • anhydride trifluoromethanesulfonic (trif
  • step (b) the activating agent is triflic anhydride.
  • step (b) is carried out at a temperature of about 0°C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl, diethylene glycol dimethyl, DMF, 1,4-dioxane, DMSO, and NMP.
  • the base is an inorganic base.
  • the base is an organic base.
  • the organic base is selected from the group consisting of DIPEA, Et?N, DABCO, and DBU.
  • the method further comprises step (c): c) reacting the final compound of step (b) with a ligand and a palladium catalyst in an aprotic solvent to produce a final compound of step (c) with the following structure:
  • step (c) is carried out at a temperature of between about 75 °C and about 80°C.
  • the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.
  • the palladium catalyst is selected from the group consisting of palladium (II) acetate (Pd(OAc)2) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12).
  • the step can comprise additional bases and other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.
  • TAA triethylamine
  • sodium bicarbonate sodium bicarbonate
  • potassium acetate potassium acetate
  • cyclohexyldiphenylphosphine cyclohexyldiphenylphosphine
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the organic base is selected from the group consisting of DIPEA, Et 3 N, DABCO, and DBU.
  • the method further comprises step (d): the presence of a base and aprotic solvent to produce a final compound of step (d) with the following structure:
  • step (d) is carried out at a temperature from about -15 °C to about 12 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the base is an organic base.
  • the organic base is selected from the group consisting of
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • An inorganic base can be used with any alkali such as lithium, sodium and potassium.
  • the inorganic base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS, LDA, and LiTMP.
  • the method further comprises step (e): e) reacting the final compound of step (d) with the final compound of step (c) in the presence of a palladium catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)-hydrochloride, and an aprotic solvent to produce a compound of the following structure:
  • step (e) is carried out at a temperature from about 60 °C to about 80 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the method further comprises step (f): f) reacting the final compound of step (e) with a fluoride salt in an aprotic solvent to produce a final compound of step (f) with the following structure:
  • step (f) is carried out at a temperature from about 25 °C to about 55 °C.
  • the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the method further comprises step (g): g) reacting the final compound of step (f) with boron trifluoride acetonitrile and an aprotic solvent to produce a final compound of step (g) with the following structure:
  • step (g) is carried out at a temperature from about 25 °C to about 45 °C.
  • the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.
  • the invention provides a method of synthesizing MRTX1133, comprising reacting with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • the invention provides a method of synthesizing MRTX1133 comprising: the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce: Boe with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • the invention provides a method of synthesizing MRTX1133 comprising: , wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce: the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:
  • the invention provides a method of synthesizing MRTX1133 comprising:
  • TIPSC1 triisopropylsilyl chloride
  • R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:
  • the invention also encompasses each of the above steps by themselves (i.e., an embodiment that is directed to step (a); an embodiment that is directed to step (b); an embodiment that is directed to step (c), etc.), as well to combinations of the steps (i.e., an embodiment that is directed to step (a) and step (b); an embodiment that is directed to steps (a), (b), and (c),
  • the invention also provides a method of synthesizing MRTX1133 comprising,
  • TIPSC1 triisopropyl silyl chloride
  • the invention also provides novel compounds of the following structures:
  • the batch is agitated at 15-20°C for 12h.
  • the reaction mass is cooled to 0-5°C then diluted with purified water (13.8 L) at 15-25°C and stirred for 10-30 minutes.
  • the phases are separated, the organic phase is washed with purified water (2x27.6 L), aqueous 20% sodium chloride (19.9 L) and filtered thru sodium sulfate (5.93 kg).
  • the cake is rinsed by DCM (6.9 L) and the filtrate containing 7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-ol (MR113340) is charged in the reactor.
  • A-Di isopropyl ethyl amine (DIPEA, 7.45 kg, 57.64 mol, 3 eq.) is charged at '5-5°C followed by triflic anhydride (8.14 kg, 28.85 mol, 1.5 eq.) at ’5-5°C.
  • the batch is agitated at 0-5°C for Ih, the reaction mass is then diluted with purified water (13.8 L) at 0-5°C.
  • the phases are separated, the organic phase is washed with purified water (19.9 L) at 15-25°C and aqueous 20% sodium chloride (19.0 L).
  • the organic solvent is removed and the reactor is charged with heptane (104 L) and methanol (69 L).
  • the heptane layer is collected and washed with methanol (34.5 L). The combined methanol layers are extracted back by heptane (34.5 L). The combined heptane layers are washed by water (19.9 L), aqueous 20% sodium chloride (19.0 L) at 15-25°C and dried over MgSC (5.93 kg) .
  • the batch is agitated at 15-20°C for 12h.
  • the reaction mass is cooled to 0-5°C then diluted with purified water (75.5 L) at 15-25°C.
  • the phases are separated, the organic phase is washed with purified water (2x109.7 kg) and brine (2x108.7 kg) at 10-25°C and filtered thru magnesium sulfate (16.23 kg).
  • the cake is washed by DCM (280.0 L) and the filtrate containing 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-ol (MR113340) is cooled to 0-5°C.
  • A,A-Diisopropylethylamine (DIPEA, 40.80 kg, 316.20 mol, 3 eq.) is charged at ’5-0°C and followed by triflic anhydride (44.60 kg, 158.10 mol, 1.5 eq.) at ’5-5°C.
  • the batch is agitated at 0-5°C for Ih, the reaction mass is then diluted with purified water (75.5 k g) at ’5-5°C.
  • the phases are separated, the organic phase is washed with purified water (108.72 kg) at 10- 25°C.
  • the solvent is removed and the reactor is charged with heptane (569.03 L) and methanol (377.5 L). After stirring for 10-30min.
  • the heptane layer is collected and washed with methanol (188.77 L). The combined methanol layers are washed back by heptane (188.77 L). The combined heptane layers are washed by water (109.48 kg).
  • MR113341 X H NMR (400 MHz, CDCh) 8 ppm 1.13 - 1.37 (m, 42H), 7.24 -
  • the catalyst Pd(dppf)Ch (0.347 kg, 0.47 mol, 0.03 eq.) andHBpin (4.08 kg, 31.88 mol, 2 eq.) are added.
  • the resulting mixture is heated to 75-80°C and stirred for 7h.
  • the crude material is cooled to 5-15°C, stirred for 2h, filtered and the cake is rinsed with acetonitrile (20.4 kg).
  • the cake is charged into second reactor followed by acetonitrile (20.4L) and stirred at 15-25°C for 2h.
  • MR113342 'H NMR (400 MHz, CDCh) 8 ppm 1.13 - 1.18 (m, 39H), 1.29 - 1.34
  • the resulting mass is diluted by acetonitrile (229.4 kg) followed by triethylamine (TEA, 27.30 kg, 269.79 mol, 3 eq.) at 15-25°C.
  • TEA triethylamine
  • the catalyst Pd(dppf)Ch (1.97 kg, 2.69 mol, 0.03 eq.) andHBpin (23.20 kg, 179.86 mol, 2 eq.) are added.
  • the resulting mixture is heated to 75-80°C and stirred for 12h.
  • the crude material is cooled to 5-15°C, stirred for 6-12h, filtered and the cake is washed with acetonitrile (91.80 kg).
  • the solid (62.60 kg) is charged back into the reactor followed by acetonitrile (183.2 kg, 4 vol) and stirred at 75-80 °C for 2h.
  • the crude material is cooled to 5-15°C, stirred for additional 6- 12h and filtered.
  • the solid is rinsed with acetonitrile (91.80 kg) and dried to afford the desired material ((6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (MR113342) as solid (46.91 kg, IY: 83.67%, purity 98.9%, KF:0.09%).
  • THF (48 L) is charged to a reactor with ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol (MR113318, 1.78 kg, 11.18 mol, 1 eq.) and ter/-butyl (lR,5S)-3- (2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113317, 4.81 kg, 11.21 mol, 1 eq.) at 10-20°C.
  • the mixture is cooled to '15-'5°C and a solution of NaHMDS in THF (5.76 kg, 2M in THF, 1.2 eq.) is slowly added at ’15-’5°C .
  • the batch is agitated for 2h at 5-12°C.
  • the reaction mass is then added to an aqueous 20% ammonium chloride (9.60 kg) at '5-0°C and the organic solvent is removed via distillation under vacuum at 30-35°C.
  • Dichloromethane (48 L) is charged in the reactor at 15-25°C. After stirring for 30 min., the phases are separated and the organic phase is collected.
  • the aqueous layer is extracted with DCM (48 L) and the combined organic layers are washed with purified water (19.2 L) and dried over MgSO4 (1.92 kg). The cake is rinsed with DCM (14.4 L) at 15-25 °C. The organic solvent is removed via distillation under vacuum at ⁇ 35°C to afford crude material (6 kg). Acetonitrile (45.8 L) is charged in the reactor, the reaction mass is heated to 75-80°C and agitated for 2h, then cooled to 15-25°C.
  • MR113317 X H NMR (400 MHz, CDC13) 3 ppm 1.53 (s, 9H), 1.66 - 1.70 (t, 2H),
  • MR113318 X H NMR (400 MHz, CDC13) 8 ppm 1.69 - 1.91 (m, 4H), 1.94 - 2.15
  • MR113319 X H NMR (400 MHz, CDCh) 8 ppm. 1.51 (s, 9H), 1.67 - 1.76 (t, 3H),
  • THF 240.70 kg
  • a reactor with ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol MR113318, 9 kg, 56.04 mol, 1 eq.
  • /c77-butyl (lR,5S)-3- (2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate MR113317, 24 kg, 56.04 mol, 1 eq.
  • the mixture is cooled to '15-'5°C and a solution of NaHMDS in THF (30.21 kg, 2M in THF, 1.2 eq.) was slowly added.
  • the batch is agitated for 2h at 5-12°C.
  • the reaction mass is then added to an aqueous solution of ammonium chloride (288 kg, 20%) at '5-0°C and the organic solvent is removed via distillation under vacuum at 30-35°C.
  • Dichloromethane (240 L) is charged in the reactor at 15-25°C; the phases are separated and the organic phase is collected.
  • the aqueous layer is extracted with DCM (240.6 L) and the combined organic layers are washed with purified water (96 L).
  • the organic solvent is removed via distillation under vacuum at ⁇ 35°C and acetonitrile (149.6 kg) is charged in the reactor. Half of the volume of acetonitrile is distilled and the reaction mass is agitated for 2-3h at 75-80°C. The suspension is filtered at 15-20°C and the solid is rinsed by acetonitrile (19.96 kg). The cake (54.63 kg) is charged back into the reactor and acetonitrile (57.2 kg, 1 vol ) is added.
  • MR113317 X H NMR (400 MHz, CDC13) 8 ppm 1.53 (s, 9H), 1.66 - 1.70 (t, 2H),
  • MR113318 J H NMR (400 MHz, CDC13) 8 ppm 1.69 - 1.91 (m, 4H), 1.94 - 2.15
  • MR113319 X H NMR (400 MHz, CDCh) 8 ppm. 1.51 (s, 9H), 1.67 - 1.76 (t, 3H),
  • the catalyst ataCXium A Pd G3 (0.32 kg, 0.44 mol, 0.15 eq.) is added, the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15-30°C n-heptane (2.4 L) is added in the reactor and the layers are separated. The aqueous layer is extracted twice by n-heptane/THF (1/4, 2x4.8 L). The combined organic layers are washed by water (4.96 L) and aqueous 20% sodium chloride solution (4 L) at 15-25°C.
  • the mixture is heated to 48-53°C and agitated for 4h. After cooling the reaction mass to 15-25°C, the mixture is fdtered and the waste cake is rinsed by toluene (46.6 L). To the fdtrate is added 16.5 wt% Ethanethiol, 2-(dimethylamino)-hydrochloride (0.53 Kg) and 33wt % silica gel (1.06 Kg, 200 - 300 mesh) at 15-25 °C. The mixture is heated to 48-53°C and stirred for 4h. After cooling the reaction mass to 15-25°C, the mixture is filtered and the waste cake is rinsed by toluene (5.5 L).
  • the catalyst ataCXium A Pd G3 (0.46 kg, 0.62 mol, 0.03 eq.) is added, the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15-30°C n- heptane (16.9 L) is added in the reactor and the layers are separated. The organic layer is washed by water (32.8 L).
  • MR113343 'H NMR (400 MHz, CDCh) 5 ppm 0.50 - 0.57 (m, 3H), 0.86 - 0.90 (t,
  • the reaction mass is diluted with water (135.8 kg) and THF (135.6 L) at 15-25°C.
  • the organic layer is collected, the aqueous layer is extracted back by a solvent mixture THF (33.9 L) and ethyl acetate (67.8L).
  • the combined organic layers are washed by aqueous 13% sodium chloride (117.0 kg) and concentrated to 67.8 L.
  • n-Heptane (406.6 L) is added and the crude mass is concentrated by distillation to 220.4 L.
  • the resulting crude is heated to 55-65°C for 2-4h, cooled to 10-20°C and stirred for an additional 12h.
  • the mass is heated to 35-40°C, when materials are dissolved, acetonitrile (28.09 kg) is introduced, followed by boron trifluoride acetonitrile solution (19wt%, 5.80 kg, 10.10 mol, 2 eq.).
  • the batch was agitated at 35-40°C for Ih.
  • the reaction mixture is cooled to 15-25°C, diluted with water (1.78 kg) and ethanol (18.21 kg). After stirring at 15-25°C for 2-5h, aqueous solution of sodium bicarbonate (6%, 35.5 kg) is slowly added and the resulting crude is stirred for 0.5h at 15-25 °C.
  • the layers are separated, the aqueous layer is extracted by DCM (23.43 kg) and the combined organic layers are concentrated to 7.1 L. The residue is diluted by ethanol (11.22 kg) and concentrated to 7.01 L. To the reaction mass are added DCM (70.84 kg) and ethanol (13.99 kg), followed by aqueous solution of sodium bicarbonate (6%, 35.5 kg). The resulting mixture is filtered thru a pad of celite (3.55 kg, 150 mesh) and the waste cake is rinsed by DCM (2.85 kg) and ethanol (0.95 kg). The filtrate layers are separated, the organic layer is washed twice by aqueous solution of sodium bicarbonate (6%, 2x35.5 kg) and aqueous solution of sodium chloride (10%, 35.5 kg).
  • the solid is dissolved in THF (53.40 kg) , filtered through silica pad (3.60 kg, 200-300 mesh) and the pad is rinsed by THF (172.41 kg). THF is removed and switch to DCM (47.91 kg). MTBE (17.76 kg) is added to DCM solution, followed by seeds (MRTX1133, 12 g). The reaction mass is concentrated to 24 L then MTBE (44.4 kg) is added over a period of 0.5h.
  • the mass is heated to 35-40°C, when all material is dissolved, acetonitrile (158.4 kg) is introduced, followed by boron trifluoride acetonitrile solution (19wt%, 36 kg, 62.79 mol, 2.2 eq.).
  • the batch was agitated at 36-43°C for 1- 3h.
  • the reaction mixture is cooled to 15-25°C, diluted with ethanol (120 L) and stirred at 15- 25°C for 2-5h.
  • Aqueous solution of potassium hydrogen carbonate (6%, 300 kg) is slowly added and the resulting crude is stirred for 2-3h at 15-25°C.
  • the reaction mass is filtered thru a pad of diatomite (150 mesh, lOKg) and the waste cake is washed by DCM (40 L).
  • the filtrate layers were separated, the aqueous layer is extracted by DCM (100 L) and the combined organic layers are diluted by potassium hydrogen carbonate (6%, 200 L) at 15-25°C. After stirring for 2-3 h, the layers are separated.
  • the bottom layer is washed with 10% aqueous NaCl (100.0 L) and dried over magnesium sulfate (4 kg).
  • the waste cake is rinsed by DCM (40.2 L) and the combined DCM layers are filtrated thru silica gel (30 kg, 75wt% with THF).
  • the silica pad is rinse by THF (1200 L).
  • the solvents are partially removed (80-100 L remained in the reactor) and the resulting solution is added to a suspension of seeds MRTX1133 (0.1 kg) in MTBE (500L).
  • the mixture is heated to 40-50°C for 12h, cooled to 15-25°C and stirred for additional l-2h.
  • the suspension is filtered, the solid is rinsed with MTBE (60 L) and dried to afford a yellow solid (14.16 kg).
  • the latter is charged back in the reactor, dissolved in DCM (85 L) and added at to a suspension of seeds MRTX1133 (71.5 g, 0.5wt%) in MTBE (354.1 L) at 40-50°C. After 24h, the suspension is cooled to 15-25°C, stirred for 2h then filtered.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouvelles voies synthétiques de synthèse de MRTX1133. L'invention concerne également des intermédiaires utilisés dans les voies de synthèse décrites.
PCT/US2024/039161 2023-07-24 2024-07-23 Procédés et intermédiaires pour la synthèse de mrtx1133 Pending WO2025024449A1 (fr)

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Cited By (1)

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WO2025231310A1 (fr) * 2024-05-03 2025-11-06 Mirati Therapeutics, Inc. Formes cristallines de mrtx1133

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CN115785124A (zh) * 2021-09-10 2023-03-14 润佳（苏州）医药科技有限公司 Kras g12d抑制剂及其用途
WO2023103523A1 (fr) * 2021-12-09 2023-06-15 苏州浦合医药科技有限公司 Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de kras g12d
WO2023134465A1 (fr) * 2022-01-11 2023-07-20 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée
CN116554208A (zh) * 2022-12-02 2023-08-08 苏州浦合医药科技有限公司 取代的双环杂芳基化合物作为kras g12d抑制剂
WO2024067714A1 (fr) * 2022-09-30 2024-04-04 泰励生物科技（上海）有限公司 Composés ayant une activité tumorale mutante anti-kras

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US20230072276A1 (en) * 2020-12-15 2023-03-09 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
CN115785124A (zh) * 2021-09-10 2023-03-14 润佳（苏州）医药科技有限公司 Kras g12d抑制剂及其用途
WO2023103523A1 (fr) * 2021-12-09 2023-06-15 苏州浦合医药科技有限公司 Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de kras g12d
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WO2023134465A1 (fr) * 2022-01-11 2023-07-20 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée
WO2024067714A1 (fr) * 2022-09-30 2024-04-04 泰励生物科技（上海）有限公司 Composés ayant une activité tumorale mutante anti-kras
CN116554208A (zh) * 2022-12-02 2023-08-08 苏州浦合医药科技有限公司 取代的双环杂芳基化合物作为kras g12d抑制剂

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WO2025231310A1 (fr) * 2024-05-03 2025-11-06 Mirati Therapeutics, Inc. Formes cristallines de mrtx1133

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